The invention relates to a new process for the synthesis of 17xcex2-hydroxy-17xcex1-methyl-1,3-seco-2-nor-5xcex1-androstane-3-acid derivatives of formula (I) 
wherein the meaning of Z is carboxyl or formyl group and
to the new secoindoxylidene carboxylic acid derivatives of formula (II) 
wherein R1 and R2 independently are C1-C4 alkyl or alkoxy group, hydrogen or halogen atomxe2x80x94which are intermediates for preparing the compounds of formula (I).
The 17xcex2-hydroxy-17xcex1-methyl-1,3 -seco-2-nor-5xcex1-androstane-3-acid derivatives of formula (I) are intermediates in the synthesis of oxandrolon (17xcex2-hydroxy-17xcex1-methyl-2-oxa-5xcex1-androstane-3-one), which is used as anabolic in therapy. The oxandrolone is used in pediatrics and for mitigation of loss of weight developing as a consequence of infections. traumas and surgical intervention. Recently the therapeutic use was extended to the improvement of the condition of AIDS patients.
Although the 17xcex2-hydroxy-17xcex1-methyl-1,3-seco-2-nor-5xcex1-androstane-3-acid derivative of formula (I). wherein the meaning of Z is carboxyl group. is described in the literature [J. Steroid Biochem. Molec. Biol. 42(2). 229-242 (1992)] as the metabolite of oxymethalone (17xcex2-hydroxy-2-hydroxymethylene-17xcex1-methyl-5xcex1-androstane-3-one) and its structure was proved by GC-MS method via a derivative of it. its synthesis and physical properties are not known.
The secoindoxylidene carboxylic acid type compounds of formula (II) are new.
The 17xcex2-hydroxy-17xcex1-methyl-1,3-seco-2-nor-5xcex1-androstane-3-acid derivative of formula (I), wherein the meaning of Z is formyl group. is known, its synthesis is described in several patents, i.e. the U.S. Pat. Nos. 3.101,349, 3,128,283 and 3,155,684, the German patent No. 1.171.425 and the French patent No. M1697. These patents describe the oxidation of 17xcex2-hydroxy-17xcex1-methyl-5xcex1-androst-1-ene-3-one with lead tetraacetate in the presence of osmium tetroxide, when 17xcex2-hydroxy-17xcex1-methyl-1-oxo-1,3-seco-2-nor-5xcex1-androstane-3-acid is obtained. The descriptions do not give yields. The use of lead tetraacetate and especially the osmium tetroxide is extremely dangerous for health and not environmental friendly. An other difficulty is that the synthesis of the starting material, the 17xcex2-hydroxy-17xcex1-methyl-5xcex1-androst-1-ene-3-one, can be carried out only in low yield by bromination of 17xcex2-hydroxy-17xcex1-methyl-5xcex1-androstane-3-one and subsequent hydrogen bromide elimination. This procedure is described i.e. in the U.S. Pat. No. 3128,283. According to the U.S. Pat. No. 3.109,016 the oxidation of the above mentioned starting material is carried out by ozone in carbon tetrachloride at xe2x88x9220xc2x0 C. to yield the mixed anhydride of 17xcex2-hydroxy-17xcex1-methyl-1-oxo-1,3-seco-2-nor-5xcex1-androstane-3-acid formed with formic acid. The oxidation was also carried out in dichloromethane in the presence of methanol to yield the methyl ester of the seco compound. The procedure does not give yields. As the use of carbon tetrachloride is restricted because of its harmful effect to health, the synthesis can not be used on industrial scale.
As can be seen from the state of arts despite the fact that there is a need for the compounds of formula (I), there is no such procedure for the synthesis of them. which can be carried out on industrial scale in good yield and without using dangerous reagents.
Surprisingly it was found, that the 17xcex2-hydroxy-17xcex1-methyl-1,3-seco-2-nor-5xcex1-androstane-3-acid derivatives of formula (I), known only as metabolites or intermediates, can be synthesized from 17xcex2-hydroxy-17xcex1-methyl-5xcex1-androstane-3-one of formula (III) 
known as mestanolone [Helv. Chim: Acta, 30(3), 867-878, (1947)]xe2x80x94by an industrially applicable method according to our invention as follows:
The 17xcex2-hydroxy-17xcex1-methyl-5xcex1-androstane-3-one of formula (III) is reacted with an aromatic nitro-aldehyde of formula (IV) 
wherein R1 and R2 independently are C1-C4 alkyl or alkoxy group, hydrogen or halogen atomxe2x80x94in a C1-C4 alcohol in the presence of aqueous alkali metal hydroxide solution,
the obtained secoindoxylidene carboxylic acid derivative of formula (II) 
wherein the meaning of R1 and R2 as defined abovexe2x80x94is separated from the reaction mixture after acidifying in given case is recrystallized from a C1-C4 alcohol or C3-C5 ketone. and oxidized using
i) for the synthesis of 17xcex2-hydroxy-17xcex1-methyl-1,3-seco-2-nor-5xcex1-androstane-3-acid derivative of formula (I), wherein Z is carboxyl group, at 15-40xc2x0 C. 2.5-5 mol equivalent, or
ii) for the synthesis of 17xcex2-hydroxy-17xcex1-methyl-1,3-seco-2-nor-5xcex1-androstane-3-acid derivative of formula (I), wherein Z is formyl group, at 15-30xc2x0 C. 1-1.5 mol equivalent alkali metal permanganate in a mixture of C1-C5 alcohol or C3-C6 ketone and aqueous alkali metal hydroxide.
The reaction of mestanolone of formula (III) and aromatic nitro-aldehyde of formula (IV) is preferably carried out in methanol as C1-C4 alcohol in the presence of potassium hydroxide. The mestanolone is preferably suspended in the mixture of the alcohol type solvent and the aqueous alkali metal hydroxide and the aromatic nitro-aldehyde of formula (IV) in alcoholic solution is added to the reaction. The addition can be carried out between 0xc2x0 C. and the reflux temperature of the reaction mixture. The completion time of the reaction depends on the temperature.
After completion of the reaction the mixture was acidified with a diluted inorganic acid till pH=0-2.5. diluted with water, the precipitated yellow crystals were filtered off, washed with aqueous alcohol and dried. The obtained secoindoxylidene carboxylic acid of formula (II), the substance content of which is 80-95%, is recrystallized in given case from a C1-C4 alcohol or C3-C5 ketone.
The recrystallized or the crude secoindoxylidene carboxylic acid of formula (II) is dissolved in a mixture of C1-C5 alcohol or C3-C6 ketone, water and aqueous alkali metal hydroxide solution (pH=10-14) and for the synthesis of 17xcex2-hydroxy-17xcex1-methyl-1,3-seco-2-nor-5xcex1-androstane-3-acid derivative of formula (I), wherein Z is carboxyl group, 2.5-5 mol equivalent of alkali metal permanganate in aqueous solution is added to the reaction at 15-40xc2x0 C. The required temperature of 15-40xc2x0 C. is kept with cooling. As the reaction proceeds the mixture turns brown. due to the precipitation of the manganese dioxide. After addition of the reagent the pH is checked and in case of deviation it is adjusted to the required value by addition of further alkali metal hydroxide solution. After completion of the reaction the precipitated manganese dioxide is filtered off or is dissolved with the addition of a reductive agent. i.e. sodium sulfite. the pH of the solution is adjusted to 5.5-6.5 and concentrated. The possible impurities precipitated from the concentrated solution are filtered off, the pH of the filtrate (which contains the desired product) is adjusted to 0-2.5 with addition of acid. The precipitated product is filtered off, washed with water and dried. The crude product is purified be suspending and stirring it in a halogenated alkan or in a mixture of a halogenated alkan and a ketone or in a ketone type solvent and subsequent filtration or recrystallization from a ketone type solvent.
If the above mentioned oxidation step is carried out the following way, instead of 17xcex2-hydroxy- 17xcex1-methyl-1,3-seco-2-nor-5xcex1-androstane-3-acid derivative of formula (1), wherein Z is carboxyl group, the 17xcex2-hydroxy- 17xcex1-methyl-1,3-seco-2-nor-5xcex1-androstane-3-acid derivative of formula (I), wherein Z is formyl group, is obtained. The reaction is carried out the same way as in the synthesis of 17xcex2-hydroxy-17xcex1-methyl-1,3-seco-2-nor-5xcex1-androstane-3-acid derivative of formula (I), wherein Z is carboxyl group, with the difference that the temperature of the oxidation is 15-30xc2x0 C. instead of 15-40xc2x0 C. and 1-1.5 mol equivalent of alkali metal permanganate is used instead of 2.5-5 mol equivalent. The crude product is purified by recrystallization from acetonitrile or from a ketone type solvent.
The oxidative cleavage of the C1-C2 double bond of secoindoxylidene carboxylic acid derivatives of formula (II) is preferably carried out in acetone, ethanol or tertiary-butanol using sodium hydroxide as base. Both oxidation reactions are preferably carried out at 20-30xc2x0 C.